Time-restricted feeding protects against septic liver injury by reshaping gut microbiota and metabolite 3-hydroxybutyrate.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro mechanistic study with supplementary human observational correlation
PubMed 40223164 · doi:10.1080/19490976.2025.2486515
What was done
Researchers investigated whether time-restricted feeding (TRF) mitigates sepsis-associated liver injury using septic mouse models, germ-free mice, liver-specific Hmgcs2 and Lpin1 knockout mice, and cultured AML12 hepatocytes. They utilized 16S rRNA sequencing, Q200 targeted metabolomics, and transcriptomic profiling. In addition, serum 3-hydroxybutyrate (3-HB) levels and gut microbiota were measured in a cohort of septic human patients to evaluate clinical correlation and diagnostic predictive capacity.
What was found
TRF enriched gut *Lactobacillus murinus*, which was otherwise depleted in septic mice. Live *L. murinus* supplementation raised circulating 3-HB and alleviated septic liver damage, an effect lost when hepatic 3-HB synthesis was blocked via *Hmgcs2* knockout. Mechanistically, 3-HB activated the PI3K/AKT/mTOR/LPIN1 pathway, reducing ACSL4, MDA, lipid peroxides (LPO), and intracellular Fe2+, thereby blocking hepatocyte ferroptosis. In septic patients, serum 3-HB correlated positively with *L. murinus* and negatively with liver injury markers, predicting septic liver injury with an area under the curve (AUC) of 0.8429.
Why it matters
This study links a dietary regimen (TRF) to gut microbial modulation and metabolite signaling (3-HB) that directly prevents hepatocyte ferroptosis during sepsis, identifying 3-HB as a potential therapeutic candidate and diagnostic biomarker.
Limits
The abstract omits exact sample sizes for both animal experiments and human cohorts. The therapeutic administration of TRF was evaluated in rodents rather than human trials, and human findings are limited to observational biomarker correlations without demonstrating that dietary timing modifies clinical sepsis outcomes.
Cited by
- supports Mice subjected to time-restricted feeding have elevated levels of ketone bodies.